Sedative Induction Agents
David A. Caro
Katren R. Tyler
INTRODUCTION
Agents used to sedate, or “induce,” patients for intubation during rapid sequence intubation (RSI) are properly called sedative induction agents because induction of general anesthesia is at the extreme of the spectrum of their sedative actions. In this chapter, we refer to this family of drugs as “induction agents.” The ideal induction agent would smoothly and quickly render the patient unconscious, unresponsive, and amnestic in one arm/heart/brain circulation time. Such an agent would also provide analgesia, maintain stable cerebral perfusion pressure and cardiovascular hemodynamics, be immediately reversible, and have few, if any, adverse side effects. Unfortunately, such an induction agent does not exist. Most induction agents meet the first criterion because they are highly lipophilic and, therefore, have a rapid onset within 15 to 30 seconds of intravenous (IV) administration. Their clinical effect is likewise terminated quickly as the drug rapidly redistributes to less well-perfused tissues. All induction agents have the potential to cause myocardial depression and subsequent hypotension. These effects depend on the particular drug; the patient’s underlying physiologic condition; and the dose, concentration, and speed of injection of the drug. The faster the drug is administered (IV push), the larger the concentration of drug that saturates those organs with the greatest blood flow (i.e., brain and heart), and the more pronounced the effect. Because RSI requires rapid administration of a preselected dose of the induction agent, the choice of drug and the dose must be individualized to capitalize on desired effects, while minimizing those that might adversely affect the patient. Some patients are so unstable that the primary goal is to produce amnesia rather than anesthesia because to produce the latter might lead to severe hypotension and organ hypoperfusion.
The induction agents include ultra-short-acting barbiturates: thiopental (Pentothal) and methohexital (Brevital); benzodiazepines: principally midazolam (Versed); and miscellaneous agents: etomidate (Amidate), ketamine (Ketalar), and propofol (Diprivan). Thiopental (Pentothal) is no longer available for clinical use in the United States, Canada, or the rest of the developed world. Other agents, such as the opioid analgesic fentanyl (Sublimaze), can function as anesthetic induction agents when used in large doses (e.g., for fentanyl 30 µg [0.03 mg] per kg); however, they are rarely, if ever, used for that purpose during emergency intubation, and so are not discussed here.
General anesthetic agents act through two principal mechanisms: (1) an increase in inhibition through γ-aminobutyric acid. A receptors (e.g., benzodiazepines, barbiturates, propofol, etomidate, isoflurane, enflurane, and halothane), and (2) a decreased excitation through N-methyl-D-aspartate (NMDA) receptors (e.g., ketamine, nitrous oxide, and xenon). Dexmedetomidine is a relatively selective α2-adrenergic agonist (like clonidine) with sedative properties, and is used in the operating room and ICU settings for procedural sedation (e.g., awake intubation), as a component of balanced anesthesia, and for the sedation of intubated patients. Dexmedetomidine is not an induction agent and its role in emergency medicine for procedural sedation is yet to be determined.
The IV induction agents discussed in this chapter share important pharmacokinetic characteristics. Induction agents are highly lipophilic and because the brain is a highly perfused, lipid dense organ, a standard induction dose of each agent in a euvolemic, normotensive patient will produce induction within 30 seconds. The blood-brain barrier is freely permeable to medications used to induce anesthesia. The observed clinical duration of each drug is measured in minutes because of the drugs’ distribution half-life (t1/2α), characterized by distribution of the drug from the central circulation to well-perfused tissues, such as brain. The redistribution of the drug from brain to fat and muscle terminates its CNS effects. The elimination half-life (t1/2β, usually measured in hours) is characterized by each drug’s reentry from fat and lean muscle into plasma down a concentration gradient leading to hepatic metabolism and renal excretion. Generally, it requires four to five elimination half-lives to completely clear the drug from the body.
The dosing of induction agents in nonobese adults should be based on ideal body weight (IBW) in kilograms. In clinical practice, the actual body weight is a reasonable enough approximation to IBW for the purposes of dosing these agents.
For obese patients, the situation is more complicated. The high lipophilicity of the induction agents combined with the increased volume of distribution (Vd) of these drugs in obesity argues for actual body weight dosing (see Chapter 39). Opposing this, however, is the significant cardiovascular depression that would occur if such a large quantity of drug is injected as a single bolus. Balancing these two considerations, and given the paucity of actual pharmacokinetic studies in obese patients, the best approach is to use Lean Body Weight (LBW) for dosing of most induction agents, decreasing to IBW if the patient is hemodynamically compromised, or for drugs with significant hemodynamic depression, such as propofol. LBW is obtained by adding 0.3 of the patient’s excess weight (actual body weight minus IBW) to the IBW, and using the sum as the dosing weight. This is in contrast to succinylcholine, which is dosed at total body weight. Drug dosing for obese patients is discussed in Chapter 39.
Aging affects the pharmacokinetics of induction agents. In elderly patients, lean body mass and total body water decrease while total body fat increases, resulting in an increased volume of distribution, an increase in t1/2β, and an increased duration of drug effect. In addition, the elderly are more sensitive to the hemodynamic and respiratory depressant effects of these agents, and the induction doses should be reduced to approximately one-half to three-fourths of the dose used in their healthy, younger counterparts.
ETOMIDATE
Etomidate (Amidate) | ||||||||||
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Clinical Pharmacology
Etomidate is an imidazole derivative that is primarily a hypnotic and has no analgesic activity. With the exception of ketamine, etomidate is the most hemodynamically stable of the currently available induction agents. It exerts its effect by enhancing GABA activity at the GABA-receptor complex, inhibiting excitatory stimuli. Etomidate attenuates underlying elevated intracranial pressure (ICP) by decreasing cerebral blood flow (CBF) and cerebral metabolic oxygen demand (CMRO2). Its hemodynamic stability preserves cerebral perfusion pressure. Etomidate may not be the most cerebroprotective of the various available induction agents (that attribute probably resides with the barbiturates), but its hemodynamic stability and favorable CNS effects make it an excellent choice for patients with elevated ICP.
Etomidate does not release histamine and is safe for use in patients with reactive airways disease. However, it lacks the direct bronchodilatory properties of ketamine, which may be a preferable agent in these patients.
Indications and Contraindications
Etomidate has become the induction agent of choice for most emergent RSIs because of its rapid onset, its hemodynamic stability, its positive effect on CMRO2 and cerebral perfusion pressure, and its rapid recovery. As with any induction agent, dosage should be adjusted in hemodynamically compromised patients. Etomidate is a U.S. Food and Drug Administration (FDA) pregnancy category C drug.
Etomidate is not FDA approved for use in children, but many series report safe and effective use in pediatric patients.
Dosage and Clinical Use
In euvolemic and hemodynamically stable patients, the normal induction dose of etomidate is 0.3 mg per kg IV push. In compromised patients, the dose should be reduced commensurate with the patient’s clinical status; reduction to 0.2 mg per kg is usually sufficient. In morbidly obese patients, the induction dose should be based on lean body weight, by using IBW and adding a correction of 30% of the weight.
Adverse Effects
Pain on injection is common because of the diluent (propylene glycol) and can be somewhat mitigated by having a fast-flowing IV solution running in a large vein. Myoclonic movement during induction is common and has been confused with seizure activity. It is of no clinical consequence and generally terminates promptly as the neuromuscular blocking agent takes effect.
The most significant and controversial side effect of etomidate is its reversible blockade of 11-β-hydroxylase, which decreases both serum cortisol and aldosterone levels. This side effect has been more common with continuous infusions of etomidate in the ICU setting than with a singledose injection used for emergency RSI. The risks and benefits of the use of etomidate in patients with sepsis are discussed in detail in the “Evidence” section at the end of the chapter.
KETAMINE
Ketamine (Ketalar) | ||||||||||
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Clinical Pharmacology
Ketamine is a phencyclidine derivative that provides significant analgesia, anesthesia, and amnesia, with minimal effect on respiratory drive. The amnestic effect is not as pronounced as that seen with the benzodiazepines. Ketamine is believed to interact with the NMDA receptors at the GABA-receptor complex, promoting neuroinhibition and subsequent anesthesia. Action on opioid receptors accounts for its profound analgesic effect. Ketamine releases catecholamines, stimulates the sympathetic nervous system, and therefore augments heart rate and BP in those patients who are not catecholamine-depleted secondary to the demands of their underlying disease. Furthermore, increases in mean arterial pressure may offset any rise in ICP, resulting in a relatively stable cerebral perfusion pressure. This is discussed in detail in the “Evidence” section. In addition to its catecholamine-releasing effect, ketamine directly relaxes bronchial smooth muscle, producing bronchodilation. Ketamine is primarily metabolized in the liver, producing one active metabolite, norketamine, which is metabolized and excreted in the urine.
Indications and Contraindications
Ketamine is the induction agent of choice for patients with reactive airways disease who require tracheal intubation. Ketamine is an excellent induction agent for patients who are hypovolemic, hypotensive, or hemodynamically unstable, including those with sepsis. In normotensive or hypertensive patients with ischemic heart disease, catecholamine release may adversely increase
myocardial oxygen demand, but it is unlikely that this effect is detrimental in patients with significant hypotension, in whom additional catecholamine release may support the blood pressure. Ketamine’s preservation of upper airway reflexes makes it appealing for awake laryngoscopy and intubation in the difficult airway patient where the dose is titrated to effect. The effects of ketamine on ICP will be discussed in the “Evidence” section. The pregnancy category of ketamine has not been established by the FDA so it is not currently recommended for use in pregnant women.
myocardial oxygen demand, but it is unlikely that this effect is detrimental in patients with significant hypotension, in whom additional catecholamine release may support the blood pressure. Ketamine’s preservation of upper airway reflexes makes it appealing for awake laryngoscopy and intubation in the difficult airway patient where the dose is titrated to effect. The effects of ketamine on ICP will be discussed in the “Evidence” section. The pregnancy category of ketamine has not been established by the FDA so it is not currently recommended for use in pregnant women.
Dosage and Clinical Use
The induction dose of ketamine for RSI is 1 to 2 mg per kg IV. In patients who are catecholamine depleted, doses >1.5 mg per kg IV may cause myocardial depression and exacerbate hypotension. For sedation, ketamine is titrated to effect beginning with 0.2 mg per kg IV. Because of its generalized stimulating effects, ketamine enhances laryngeal reflexes and increases pharyngeal and bronchial secretions. These secretions may uncommonly precipitate laryngospasm, and may interfere with upper airway examination during awake intubation, but are not an issue during RSI. Atropine 0.01 mg per kg IV or glycopyrrolate (Robinul) 0.01 mg per kg IV may be administered 15 to 20 minutes before ketamine to promote a drying effect for awake intubation, when feasible. Ketamine is available in three separate concentrations: 10, 50, and 100 mg per ml. Care should be taken to ensure that only one concentration is stored in the emergency department.
Adverse Effects
Hallucinations may occur on emergence from ketamine and are more common in the adult than in the child. They may be attenuated by the concomitant or subsequent administration of a benzodiazepine, if desired. Such emergence reactions occur infrequently in the emergency department as most patients are subsequently sedated with either a benzodiazepine, or with propofol, after the airway has been secured.
PROPOFOL
Propofol (Diprivan) | ||||||||||
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Clinical Pharmacology
Propofol is an alkylphenol derivative (i.e., an alcohol) with hypnotic properties. It is highly lipid soluble. Propofol enhances GABA activity at the GABA-receptor complex. It decreases CMRO2 and ICP. Propofol does not cause histamine release. Propofol causes a reduction in BP through vasodilation and direct myocardial depression. The ensuing hypotension, or the resultant decrease in cerebral perfusion pressure, may be detrimental in a compromised patient. The manufacturer recommends that rapid bolus dosing (either single or repeated) be avoided in patients who are elderly, debilitated, or ASA Class III or IV in order to minimize undesirable cardiovascular depression, including hypotension. It must be used cautiously for emergency RSI in hemodynamically unstable patients.
Indications and Contraindications
Propofol is an excellent induction agent in a stable patient. Its adverse potential for hypotension and reduction in cerebral perfusion pressure limits its role as an induction agent in emergent RSI. Propofol has been used successfully as an induction agent during tracheal intubation for reactive airways disease. There are no absolute contraindications to the use of propofol. Propofol is delivered as an emulsion in soybean oil and lecithin. Patients who are allergic to eggs generally react to the ovalbumin and not to lecithin, so propofol is not contraindicated in patients with egg allergy. Propofol is a pregnancy category B drug, and has become the induction agent of choice in pregnant patients.
Dosage and Clinical Use
The induction dose of propofol is 1.5 mg per kg IV in a euvolemic, normotensive patient. Because of its predictable tendency to reduce mean arterial BP, doses are reduced by 1/3 to 1/2 when propofol is given as an induction agent for emergency RSI in compromised or elderly patients.
Adverse Effects
Propofol causes pain on injection, which can be attenuated by injecting the medication through a rapidly running IV in a large vein (e.g., antecubital). Premedication of the vein with lidocaine (2 to 3 ml of 1% lidocaine) will also minimize the pain of injection. Propofol and lidocaine are compatible in the same syringe and can be mixed in a 10:1 ratio (10 ml of propofol to 1 ml of 1% lidocaine). Propofol can cause mild clonus to a greater degree than thiopental, but less than etomidate or methohexital. Venous thrombophlebitis at the injection site may occasionally occur.
METHOHEXITAL
Ultra-Short-Acting Barbiturates | ||||||||||||
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Clinical Pharmacology
Thiopental was once the prototypical barbiturate used for anesthetic induction. In January 2011, however, thiopental was removed from clinical use in the United States, Canada, the United Kingdom, Australia, and New Zealand, citing concerns from the manufacturer that clinical supplies could be used in lethal injection. Methohexital is a close relative of thiopental and remains in clinical use. Both are ultra-short-acting CNS depressants that induce hypnosis (sleep) but not analgesia. Recovery after a small dose is rapid with some somnolence and retrograde amnesia. Repeated IV doses lead to prolonged anesthesia because fatty tissues act as a reservoir. Methohexital is two to three times more potent than thiopental, 1.5 mg of methohexital being equal to 4 mg of thiopental. The t1/2β for methohexital is shorter than that for thiopental.
At low doses, ultra-short-acting barbiturates decrease GABA dissociation from its receptor, which enhances GABA’s neuroinhibitory activity. At higher doses, they can directly stimulate the GABA receptor itself. Barbiturates are cerebroprotective, causing a dose-dependent decrease in cerebral metabolic oxygen consumption and a parallel decrease in CBF and ICP, provided cerebral perfusion pressure is maintained.
Thiopental and methohexital are largely degraded in the liver. Neither have active metabolites.
Indications and Contraindications
Thiopental was widely used as an induction agent in the past, but it has largely been supplanted by etomidate and propofol. It is currently unavailable for clinical use. Methohexital is primarily used for procedural sedation and is rarely used for induction.
Dosage and Clinical Use
The dosing of ultra-short-acting barbiturates depends on the hemodynamic status of the patient and the concomitant use of other agents in RSI. The recommended induction dose of methohexital in the euvolemic, normotensive patient is 1.5 mg per kg IV. For procedural sedation or an assisted laryngoscopy, half this dose should be used.
The ultra-short-acting barbiturates should be avoided entirely in frankly hypotensive patients for whom other drugs, such as etomidate or ketamine, may preserve greater hemodynamic stability. With the widespread adoption of etomidate, which has significant cardiovascular stability, the ultra-short-acting barbiturates are rarely used as induction agents for emergent RSI.
Adverse Effects
The principal side effects of barbiturates include central respiratory depression, venodilation, and myocardial depression. Barbiturates cause a dose-related release of histamine that rarely is clinically significant, but may cause or exacerbate bronchospasm in patients with reactive airways disease. Ketamine is the preferred induction agent for patients with reactive airways disease. Methohexital causes more excitatory phenomena (twitching and hiccups) than thiopental.
Inadvertent intra-arterial injection or subcutaneous extravasation of ultra-short-acting barbiturates can result in chemical endarteritis and distal thrombosis, ischemia, and tissue necrosis because they have a highly alkaline pH (>10). If extravasation occurs, 40 to 80 mg of papaverine (Cerespan) in 20 ml normal saline or 10 ml of 1% lidocaine (Xylocaine) should be injected intraarterially proximal to the site to inhibit smooth muscle spasm. Consider local infiltration of an α-adrenergic blocking agent, such as phentolamine, into the vasospastic area.
BENZODIAZEPINES
Short-Acting Benzodiazepines | ||
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